US8283339B2 - Vinyl phosphonate lysophosphatidic acid receptor antagonists - Google Patents

Vinyl phosphonate lysophosphatidic acid receptor antagonists Download PDF

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US8283339B2
US8283339B2 US12/357,728 US35772809A US8283339B2 US 8283339 B2 US8283339 B2 US 8283339B2 US 35772809 A US35772809 A US 35772809A US 8283339 B2 US8283339 B2 US 8283339B2
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aryl
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US20090197835A1 (en
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Karen M. Carter
Kevin R. Lynch
Timothy L. MacDonald
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UVA Licensing and Ventures Group
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University of Virginia Patent Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • Lysophosphatidic acids are lysophospholipid mediators that can evoke a variety of responses when applied to living mammalian cells. These include calcium mobilization, changes in the cytoskeleton that may lead to increased migration, increased cell survival, resistance to apoptosis and mitogenesis. LPA is also believed to promote platelet aggregation in a number of mammalian species including humans. Further, LPA is a pro-angiogenic factor. LPA signals through a set of at least three G protein-coupled receptors, named LPA 1 , LPA 2 and LPA 3 (formerly EDG2, EDG4 and EDG7). Other receptors for LPA, including the G protein-coupled receptors GPR23 and GPR92 and a nuclear hormone receptor (PPAR- ⁇ ) have been suggested.
  • PPAR- ⁇ nuclear hormone receptor
  • LPA is an intermediate that is present during phospholipid biosynthesis in all cells. It is made via a common de novo phospholipid biosynthetic pathway.
  • Extracellular (plasma) LPA is derived mainly by the action of the plasma phosphodiesterase, autotaxin (ENPP-2), on lysophosphatidylcholine (LPC).
  • LPA levels in human plasma are reported to be in the range of about 200-600 nanomolar (nM).
  • nM nanomolar
  • LPA in serum is derived, directly and indirectly, from activated platelets. Serum LPA concentrations are in the range of about 2-6 micromolar ( ⁇ M).
  • Extracellular LPA accumulation is characteristic of the ascitic fluid often associated with human ovarian cancer. LPA is believed to be a pro-mitogenic stimulus for the ovarian cancer cells. LPA concentrations in these malignant ascites has been reported to be in the range of about 2-50 ⁇ M.
  • LPA has been suggested to have a role in preventing the progression of neoplastic diseases.
  • the lack of suitable LPA receptor antagonist molecules has made this difficult to prove.
  • LPA is angiogenic in a chicken chorioallantoic membrane model, which suggests a role of LPA signaling in angiogenic processes such tumor development.
  • Mice wherein the LPA, receptor gene is deleted do not develop neuropathic pain normally, which suggests a role for this receptor type in development of neuropathic pain.
  • the present invention provides in one aspect compounds that have antagonist activity at one or more of the LPA receptors.
  • the compounds are LPA analogs that can behave as antagonists at LPA receptors. Accordingly, there is provided a compound of formula I:
  • Z is —CY ⁇ CH— or —C ⁇ C—; wherein when Z is —CY ⁇ CH— then the double bond is in the trans (e) configuration;
  • Y is hydrogen or halogen, each R 1 is independently halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , or cyano; and R 2 is hydrogen, halo, (C 1 -C 12 )alkyl, halo(C 1 -C 12 )alkyl, halo(C 1 -C 12 )alkoxyl, (C 3 -C 12 )cycloalkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, —NH 2
  • Each R 3 is independently halo, (C 1 -C 12 )alkyl, halo(C 1 -C 12 )alkyl, halo(C 1 -C 12 )alkoxyl, (C 3 -C 12 )cycloalkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, —NH 2 , —NH(C 1 -C 12 )alkyl, —N((C 1 -C 12 )alkyl) 2 , (C 6 -C 10 )aryl, (C 1 -C 12 )alkyl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 12 )alkyl, or aryl-substituted aryl(C 1 -C 12 )alkyl.
  • R 4 is (C 6 -C 24 )alkyl, halo(C 6 -C 24 )alkyl, (C 6 -C 24 )alkoxy, —NH 2 , —NH(C 1 -C 24 )alkyl, —N((C 1 -C 24 )alkyl) 2 , cyano, (C 3 -C 10 )cycloalkyl, (C 4 -C 15 )bicycloalkyl, (C 6 -C 24 )alkenyl, (C 6 -C 24 )-alkynyl, (C 6 -C 10 )aryl, (C 12 -C 34 )alkyl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 12 -C 34 )alkyl, or (C 6 -C 10 )aryl-substituted (C 6 -C 10 )aryl(C 12 -C 34 )alkyl;
  • R 5 and R 6 are independently hydroxy, (C 1 -C 12 )alkyl-O—, (C 2 -C 12 )alkenyl-O—, (C 2 -C 12 )alkynyl-O—, (C 6 -C 10 )aryl-O—,
  • n 0, 1, 2, or 3; or a pharmaceutically acceptable salt or ester thereof.
  • the present invention also provides esters of any of the compounds having formula I having an ester function added to form pro-drugs to increase oral availability.
  • the invention also provides compounds of formula (I) for use in medical therapies.
  • the present invention also provides:
  • the invention provides a method for reducing damage resulting from an ischemia-reperfusion injury.
  • an ischemia-reperfusion injury include myocardial infarction, ischemic stroke, an ischemic-reperfusion injury to the kidney and the like
  • the method includes administration of an effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof to a patient in need thereof (for example, a human).
  • the invention provides the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof to prepare a medicament for inhibiting tumor growth, metastasis or tumor angiogenesis in a mammalian species (for example, a human).
  • the invention provides a compound of formula I, a pharmaceutically acceptable salt or ester thereof for use in medical treatment (for example, treatment of neoplastic disease, inhibiting tumor growth, treatment of neuropathic pain, or treating vascular injuries or treatment of an ischemia-reperfusion injury).
  • medical treatment for example, treatment of neoplastic disease, inhibiting tumor growth, treatment of neuropathic pain, or treating vascular injuries or treatment of an ischemia-reperfusion injury.
  • the invention provides pro-drugs of the compounds of formula I.
  • the invention also provides pharmaceutically acceptable salts or esters of compounds of formula I for use in medial therapy.
  • the invention provides for the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof to prepare a medicament for treating neuropathic pain in a mammalian species (for example, a human).
  • the invention provides a method for the use of a compound of formula I, a pharmaceutically acceptable salt or ester thereof to prepare a medicament for inhibiting tumor growth, metastasis or tumor angiogenesis in a mammalian species (for example, a human).
  • the present invention provides compositions and methods for the use of LPA analogs and LPA pro-drugs for the treatment of neoplastic disease.
  • this treatment is effected by application of LPA receptor antagonists that are efficacious by virtue of their anti-angiogenic properties.
  • the invention includes also a method for binding a compound of formula I (e.g., LPA 1 /LPA 3 receptor antagonists) to designated receptor sites comprising in vivo or in vitro, with an amount of a compound of formula I effective to bind said receptors.
  • Tissue having ligand bound designated LPA receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent.
  • the invention provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I, including the generic and specific intermediates as well as the synthetic processes described herein.
  • the present invention provides synthetic schemes and methods of use of compounds having formula I and analogs or derivatives thereof.
  • the invention provides synthetic and modification schemes for preparing analogs and derivatives of the compounds of formula I, as well as compositions and methods for the use of such analogs and derivatives.
  • FIGS. 1A and 1B illustrate a general synthesis of the LPA antagonists.
  • FIG. 2 is a graphic representation of LPA-driven calcium mobilization in A431 cells.
  • FIG. 3 is a graphic representation of LPA-driven adenylyl cyclase inhibition in C6 glioma cells.
  • FIG. 4 illustrates LPA-driven cell migration in A2058 cells.
  • FIG. 5 , FIGS. 6A and 6B illustrate melanoma tumor growth.
  • FIG. 7 illustrates the quantification of the extent of angiogenesis in a tumor.
  • FIGS. 8A-8D illustrate the ability of the disclosed compounds to prevent angiogenesis in tumors.
  • FIGS. 9A-9C illustrate the effect of the disclosed compounds on tactile allodynia and thermal hyperalgesia in rats wherein ligatures have been placed on the sciatic nerve.
  • FIGS. 10 a - 10 ii , 11 a - 11 mm , and 12 a - 12 nn illustrate the effect of a test compound on tumor growth.
  • FIGS. 13A-13D illustrate the effects of a test compound on lytic bone metastasis.
  • GPCR G-protein coupled receptor
  • SAR structure-activity relationship
  • LPA lysophosphatidic acid
  • LPA 1 , LPA 2 , LPA 3 LPA receptor types
  • EDG endothelial cell differentiation gene
  • RT-PCR reverse transcriptase polymerase chain reaction
  • compositions that comprises “an” element means one element or more than one element.
  • receptor agonists are compounds that mimic the action of LPA at one or more of its receptors but may have differing potency and/or efficacy.
  • receptor antagonists are compounds that 1) lack intrinsic agonist activity and 2) block agonist (e.g., LPA) activation of the LPA receptor(s), often in a manner that is both fully surmountable and reversible (‘competitive antagonist’).
  • affected cell refers to a cell of a subject afflicted with a disease or disorder, which affected cell has an altered phenotype relative to a subject not afflicted with a disease or disorder.
  • Cells or tissue are “affected” by a disease or disorder if the cells or tissue have an altered phenotype relative to the same cells or tissue in a subject not afflicted with a disease or disorder.
  • a disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • an “analog” of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5-fluorouracil is an analog of thymine).
  • a “control” cell, tissue, sample, or subject is a cell, tissue, sample, or subject of the same type as a test cell, tissue, sample, or subject.
  • the control may, for example, be examined at precisely or nearly the same time the test cell, tissue, sample, or subject is examined.
  • the control may also, for example, be examined at a time distant from the time at which the test cell, tissue, sample, or subject is examined, and the results of the examination of the control may be recorded so that the recorded results may be compared with results obtained by examination of a test cell, tissue, sample, or subject.
  • the control may also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a disease or disorder for which the test is being performed.
  • test cell tissue, sample, or subject is one being examined or treated.
  • a “pathoindicative” cell, tissue, or sample is one which, when present, is an indication that the animal in which the cell, tissue, or sample is located (or from which the tissue was obtained) is afflicted with a disease or disorder.
  • the presence of one or more breast cells in a lung tissue of an animal is an indication that the animal is afflicted with metastatic breast cancer.
  • a tissue “normally comprises” a cell if one or more of the cell are present in the tissue in an animal not afflicted with a disease or disorder.
  • a “detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound having the marker in the presence of similar compounds without a marker.
  • Detectable markers or reporter molecules include, e.g., radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and molecules that provide for altered fluorescence-polarization or altered light-scattering.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • an “effective amount” means an amount sufficient to produce a selected effect.
  • an effective amount of an LPA receptor antagonist is an amount that decreases the cell signaling activity of the LPA receptor.
  • a “functional” molecule is a molecule in a form in which it exhibits a property by which it is characterized.
  • a functional enzyme is one which exhibits the characteristic catalytic activity by which the enzyme is characterized.
  • inhibitor refers to the ability of a disclosed compound to reduce or impede a described function. Preferably, inhibition is by at least 10%, more preferably by at least 25%, even more preferably by at least 50%, and most preferably, the function is inhibited by at least 75%.
  • “Instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the disclosed compounds in the kit for effecting alleviation of the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit may, for example, be affixed to a container which contains a disclosed compound or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • purified and similar terms relate to the isolation of a molecule or compound in a form that is substantially free (at least 75% free, preferably 90% free, and most preferably at least 95% free) from other components normally associated with the molecule or compound in a native environment.
  • purified does not necessarily indicate that complete purity of the particular molecules achieved during the process.
  • a “very pure” compound refers to a compound that is greater than 90% pure.
  • a “highly purified” compound refers to a compound that is greater than 95% pure.
  • sample refers preferably to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine.
  • a sample can also be any other source of material obtained from a subject, which contains cells, tissues, or fluid of interest.
  • a sample can also be obtained from cell or tissue culture.
  • Standard refers to something used for comparison.
  • a standard can be a known standard agent or compound which is administered or added to a control sample and used for comparing results when measuring said compound in a test sample.
  • Standard can also refer to an “internal standard,” such as an agent or compound that is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
  • a “subject” of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably a human.
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • a “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • treating includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition or preventing or eliminating said symptoms.
  • the disclosed compounds are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, “rt” for room temperature, and “rac” for racemic mixture).
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • the disclosed compounds include compounds of formula I having any combination of the values, specific values, more specific values, and preferred values described herein.
  • halogen or “halo” includes bromo, chloro, fluoro, and iodo.
  • haloalkyl refers to an alkyl radical bearing at least one halogen substituent, non-limiting examples include, but are not limited to, chloromethyl, fluoroethyl or trifluoromethyl and the like.
  • C 1 -C 24 alkyl refers to a branched or linear alkyl group having from one to nine carbons.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • C 2 -C 24 alkenyl refers to an olefinically unsaturated branched or linear group having from two to nine carbon atoms and at least one double bond.
  • C 2 -C 24 alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, hexenyl, heptenyl, octenyl and the like.
  • (C 2 -C 24 )alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl, and the like.
  • (C 1 -C 24 )alkoxy or alkoxyl refers to an alkyl group attached through an oxygen atom.
  • Examples of (C 1 -C 24 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy and the like.
  • the term; (C 2 -C 26 )alkoxyalkyl can be methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like.
  • C 3 -C 12 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • (C 6 -C 10 )aryl refers to a mono or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • (C 6 -C 10 )aryl(C 1 -C 24 )alkyl refers to an alkyl group substituted with a mono or bicyclic carbocyclic ring system having one or two aromatic rings including, a group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • arylalkyl include benzyl, phenylethyl, naphthylmethyl and the like.
  • (C 1 -C 24 )alkyl(C 6 -C 10 )aryl refers to any aryl group that is attached to the parent moiety via the alkyl group, and the term “(C 1 -C 24 )alkyl(C 6 -C 10 )aryl” to an aromatic ring that is attached to the parent moiety via an alkyl group.
  • aryl includes aryl compounds having zero, one, two, three or four substituents
  • a substituted aryl includes aryl compounds having one, two, three or four substituents, wherein the substituents include groups such as, for example, alkyl, halo, or amino substituents.
  • the “(C 2 -C 10 )heterocyclic group” refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing one, two, or three heteroatoms (optionally in each ring) wherein the heteroatoms are oxygen, sulfur, and nitrogen.
  • heteroaryl refers to an optionally substituted mono- or bicyclic carbocyclic ring system containing one, two, or three heteroatoms (optionally in each ring) wherein the heteroatoms are oxygen, sulfur, and nitrogen.
  • heteroaryl groups include furyl, thienyl, pyridyl, and the like.
  • bicyclic represents either an unsaturated or saturated stable bridged or fused bicyclic carbon ring.
  • the bicyclic ring may be attached at any carbon atom which affords a stable structure.
  • a bicyclic ring system can have from about 7- to about 12 atoms in the ring system.
  • the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
  • phosphate analog comprise analogs of phosphate and phosphonate wherein the phosphorous atom is in the +5 oxidation state and one or more of the oxygen atoms is replaced with a non-oxygen moiety, including for example, the phosphate analogs phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, phosphoramidate, boronophosphates, and the like, including associated counterions, e.g., H, NH 4 , Na, K, and the like if such counterions are present.
  • counterions e.g., H, NH 4 , Na, K, and the like if such counterions are present.
  • a “derivative” of a compound refers to a chemical compound that may be produced from another compound of similar structure in one or more steps, such as replacement of hydrogen by an alkyl, acyl, or amino group.
  • pharmaceutically acceptable carrier includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, hydroxypropyl beta-cyclodextrins (HO-propyl beta cyclodextrins), water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • a phosphate buffered saline solution hydroxypropyl beta-cyclodextrins (HO-propyl beta cyclodextrins)
  • water emulsions such as an oil/water or water/oil emulsion
  • emulsions such as an oil/water or water/oil emulsion
  • wetting agents such as an oil/water or water/oil emulsion
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
  • pharmaceutically-acceptable salt refers to salts that retain the biological effectiveness and properties of the disclosed compounds and that are not biologically or otherwise undesirable.
  • the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto.
  • an “effective amount” means an amount sufficient to produce a selected effect.
  • an effective amount of an LPA receptor agonist is an amount that decreases the cell signaling activity of the LPA receptor.
  • the disclosed compounds may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • the following structure :
  • 16:0, 18:0, 18:1, 20:4 or 22:6 hydrocarbon refers to a branched or straight alkyl or alkenyl group, wherein the first integer represents the total number of carbons in the group and the second integer represent the number of double bonds in the group.
  • LPA modulating agent refers a compound or composition that is capable of inducing a detectable change in LPA receptor activity in vivo or in vitro (e.g., at least 10% increase or decrease in LPA activity as measured by a given assay such as the bioassay described in the examples and known in the art.
  • LPA receptor refers to all of the LPA receptor subtypes (for example, the LPA receptors LPA 1 , LPA 2 , and LPA 3 ), unless the specific subtype is indicated.
  • the disclosed compounds can contain one or more asymmetric centers in the molecule.
  • any structure that does not designate the stereochemistry is to be understood as embracing all the various optical isomers, as well as racemic mixtures thereof.
  • the disclosed compounds having chiral centers may exist in and be isolated in optically active and racemic forms. It is to be understood that the disclosed compounds encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the compound, which possess the useful properties described herein, such as the S,R; S,S; R,R; or R,S diastereomers.
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase
  • LPA agonist activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • some compounds may exhibit polymorphism.
  • Neuropathic pain is characterized by its chronic nature, an absence of an obvious, direct cause (e.g., tissue damage), hyperalgesia or allodynia.
  • Hyperalgesia is an exaggerated response to a painful stimulus. Allodynia is the perception of normal stimuli as painful (examples include the touch of clothing, warm or cool air, etc.).
  • Neuropathic pain can be a sequel to nerve damage in an extremity such as an arm, or more often a leg.
  • Precipitating events can include trauma, e.g., motor vehicle accidents or amputations (e.g., phantom limb pain).
  • Neuropathic pain can occur due to an adverse effect of drug therapies, e.g., vincristine or paclitaxel (TAXOLTM) or can occur as a component of disease pathologies, such as diabetes type 1 or type2, shingles, HIV-1 infections, etc.
  • drug therapies e.g., vincristine or paclitaxel (TAXOLTM) or can occur as a component of disease pathologies, such as diabetes type 1 or type2, shingles, HIV-1 infections, etc.
  • neuropathic pain is not responsive to opiates or non-steroidal anti-inflammatory drugs such as aspirin.
  • the present invention provides compositions and methods for the use of the LPA analogs of the invention to prevent, inhibit, or treat neuropathic pain by agonizing or antagonizing the LPA receptors.
  • Pain can be nociceptive or neuropathic in nature.
  • Neuropathic pain is characterized by its chronic nature, an absence of an obvious, direct cause (i.e., tissue damage), and allodynia. Allodynia is the perception of normal stimuli as painful (examples include the touch of clothing, warm or cool air, etc.).
  • Neuropathic pain is often a sequel to nerve damage in an extremity such as an arm, or more often, a leg.
  • neuropathic pain is not responsive to opiates or non-steroidal anti-inflammatory drugs such as aspirin.
  • the present invention provides compositions and methods for the use of LPA analogs and LPA pro-drugs for the treatment of neoplastic disease.
  • this treatment is effected by application of LPA receptor antagonists that are efficacious by virtue of their anti-angiogenic properties.
  • the treatment is effected by administration of sphingosine analogs that inhibit the multiple substrate lipid kinase.
  • the present invention is also includes pharmaceutical compositions including the compounds of the present invention. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition having a compound of the invention, or analog, derivative, or modification thereof, as described herein, is used to administer the appropriate compound to a subject.
  • the compounds of the invention are useful for treating a disease or disorder including administering to a subject in need thereof of a therapeutically acceptable amount of a compound of formula I, or a pharmaceutical composition including a therapeutically effective amount of a compound of formula I, and a pharmaceutically-acceptable carrier.
  • the present invention is directed to lysophosphatidic acid (LPA) analogs that have activity as receptor antagonists at one or more LPA receptors, specifically LPA 1 , LPA 2 , and LPA 3 receptor types.
  • LPA lysophosphatidic acid
  • the invention includes both compounds that have a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates particularly where the alpha substitution is a halogen and phosphothionates.
  • Z is —CY ⁇ CH—.
  • Y is hydrogen, fluorine, chlorine or bromine.
  • Y is hydrogen or fluorine.
  • Another exemplary value for Y is hydrogen.
  • Another exemplary value for Y is fluorine.
  • R 1 examples include fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, or (C 1 -C 6 )alkyl substituted with, alkoxy or cyano.
  • R 1 Additional exemplary values for R 1 include fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy.
  • R 3 Exemplary values for R 3 include fluorine, chlorine, bromine, trifluoro-methyl, methoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, or (C 1 -C 6 )alkyl substituted with, alkoxy or cyano.
  • R 3 Additional exemplary values for R 3 include fluorine, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, or ethoxy.
  • Exemplary values for R 4 include alkyl, or alkenyl.
  • R 2 Exemplary values for R 2 include hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, 1,1,1-trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, and pentoxy.
  • Exemplary values for R 2 include hydrogen, trifluoromethyl, trifluoromethoxy, 1,1,1-trifluoroethyl, and 1,1,1-trifluoroethoxy.
  • R 2 Additional exemplary values for R 2 include hydrogen, trifluoromethoxy, and 1,1,1-trifluoroethoxy.
  • R 4 Additional exemplary values for R 4 include C 5 H 11 , C 6 H 13 , C 7 H 14 CH ⁇ CHC 8 H 17 and C 15 H 31 .
  • R 4 Additional exemplary values for R 4 include C 7 H 14 CH ⁇ CHC 8 H 17 and C 15 H 31 .
  • Exemplary values for R 5 , and R 6 include trifluoromethoxy, 1,1,1-trifluoroethoxy, methoxy, and ethoxy.
  • R 5 and R 6 include hydroxy, methoxy, and ethoxy.
  • Values for R 3 include methyl, hydroxymethyl, ethyl, hydroxyethyl, propyl, hydroxypropyl, or isopropyl.
  • R 3 is methyl, hydroxymethyl, ethyl, or hydroxyethyl.
  • R 4 includes is hydroxy, or phosphate (—OPO 3 H 2 ).
  • compositions of formula I are sufficiently basic or acidic to form stable nontoxic acid or base salts
  • preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Salts from inorganic bases include but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, di(cycloalkyl) amines, tri(cycloal
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • Non-limiting examples of amines include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least about 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders having the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium including, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Exemplary solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) of formula I in a liquid composition will be from about 0.1 to about 25 weight percent, preferably from about 0.5-10 weight percent.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 weight percent preferably about 0.5-2.5 weight percent based on the total weight of the composition.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the disclosed method includes a kit including an inhibitor compound of formula I and instructional material that describes administering the inhibitor compound or a composition including the inhibitor compound to a cell or a subject.
  • a kit including an inhibitor compound of formula I and instructional material that describes administering the inhibitor compound or a composition including the inhibitor compound to a cell or a subject.
  • the subject is a human.
  • Processes for preparing compounds of formula I or for preparing intermediates useful for preparing compounds of formula I are provided as further embodiments. Intermediates useful for preparing compounds of formula I are also provided as further embodiments. The processes are provided as further embodiments and are illustrated in the schemes herein wherein the meanings of the generic radicals are as given above unless otherwise qualified.
  • a general method for preparing the disclosed compounds is illustrated in Scheme 1 and Scheme 2, illustrated in FIGS. 1A and 1B , respectively.
  • Nuclear magnetic resonance spectra were collected using a Varian Unity spectrometer at 300 MHz and chemical shifts are reported in ppm and coupling constant, J, is reported in Hz.
  • Mass spectrometry was collected using a Finnigan (model LCQ Classic) quadrupole ion trap mass spectrometer.
  • This product has similar spectral properties as its enantiomer.
  • N-Boc or N-Fmoc, O-TBS, tyrosine OMe (10.2 mmol) in anhydrous toluene (100 ml), cooled to ⁇ 78° C. is added DIBAL-H (1M in hexanes, 30.5 ml, 30.5 mmol) over 45 minutes via cannulation. The reaction is stirred an additional 5 minutes and quenched with MeOH. The mixture is removed from cooling bath, saturated aqueous Rochelle's salt (150 ml) is added and the mixture stirred vigorously for 1.5 hours or until the phases become clear. The mixture is extracted with ether, and the ethereal extract is washed with brine, dried over MgSO 4 ), and concentrated under reduced pressure to give the aldehyde as a glassy solid which is used without further purification.
  • Method B To a solution of NaH (60% in mineral oil, 375 mg, 9.4 mmol) in THF (15 ml) at 0° C. is added the appropriate tetra-ethyl diphosphonate (9.4 mmol) in THF (15 ml) via cannulation. The mixture is stirred at 0° C. for 30 min and the aldehyde, dissolved in THF (25 ml), is added via cannulation. The mixture is allowed to stir an additional 30 minutes at 0° C. Excess NaH is consumed with saturated aqueous ammonium chloride, and the aqueous layer is extracted with Ethyl Acetate.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • This product has similar spectral properties as its enantiomer.
  • Rat glioma C62B cells accumulate cAMP in response to isoproterenol, and this stimulation of adenylyl cyclase is blocked by LPA. As shown, the LPA inhibition of adenylyl cyclase activation is relieved by addition of VPC51299, VPC52172, VPC52173, and VPC52178, all in a dose-dependent manner. Results are illustrated in FIG. 3 .
  • Human melanoma A2058 cells (1 ⁇ 10 5 ) were placed in the upper portion of a modified Boydon chamber. The indicated compounds were placed in the lower chamber and after four hours at 37° C., cells were collected from the underside of the membrane (8 ⁇ m pore size, Matrigel® coated) and their mass determined. Results are illustrated in FIG. 4 .
  • Fertilized chicken eggs were windowed on day 3 of embryonic development to expose the chorioallantoic membrane. After a further 4 days of incubation, a 5 mm diameter plug of filter paper (Whatman GF/C) was applied to the membrane and soaked with 20 microliters of either vehicle (3% fatty acid free bovine serum albumin (FAF_BSA) or compound dissolved in vehicle at the indicated concentration. Application of the solutions was repeated daily for 3 days (embryonic days 7-9). On embryonic day 10, filter paper plugs were removed, the underlying membrane excised and fixed in formalin and examined microscopically. Quantification was achieved by counting the number of small diameter vessels that run perpendicular to the disk image. Results are illustrated in FIG. 7 and FIGS. 8A-8D .
  • CCI chronic constriction injury
  • VPC51299 was effective in relieving some of the thermal hyperalgesia and mechanical allodynia associated with CCl.
  • rats receiving VPC51299 withdrew their paw 3.1 seconds slower than vehicle treated rats, lifted their paw 3.2 fewer times (out of 10 trials) than vehicle treated rats, and had a withdrawal threshold 4.0 g. higher than vehicle treated rats.
  • mice were inoculated with 5 million HM7 cells in PBS, in a 0.2 ml volume per mouse, in the lower right dorsal flank area, SQ.
  • animals were randomly divided into 3 groups of 10, including vehicle (2% hydroxypropyl beta cyclodextrin), oral dose of 0.5 ml, FTY720 (10 mg/kg) oral dose of 0.5 ml, and compound 51299 (15 mg/kg) SQ dose of 0.1 ml.
  • MICROFILTM (Carver, Mass.), a commercially available lead chromate latex, was prepared as recommended by the manufacturer and perfuse at a rate of 2 ml/min for 17 ml.
  • the infused latex mixture was allowed to polymerize at room temperature for sixty minutes before dissection of tissues of interest. Dissected tumors were immersed in 10% neutral buffered formalin.
  • the tumors were then imaged with a ⁇ CT40 (SCANCO Medical, Basserdorf, Switzerland) x-ray micro-computed tomography (micro-CT) system.
  • the tumors were imaged with soybean oil as the background media.
  • the micro-CT images were generated by operating the x-ray tube at an energy level of 45 kV, a current of 177 ⁇ A and an integration time of 450 ms.
  • Axial images were obtained at an isotropic resolution of 16 ⁇ m.
  • the vascular network and tumor were extracted by a series of image processing steps.
  • An intensity threshold of 1195 Houndsfield Units (HU) and morphological filtering (erosion and dilation) were applied to the volumetric micro-ct image data to extract the vascular volume (VV).
  • the tumor volume (TV) was extracted from the background in similar fashion with an intensity threshold of ⁇ 8 HU.
  • Vessel density (VV/TV) was determined from the ratio of VV to TV.
  • the vascular and tumor intensity thresholds were determined by visual inspection of the segmentation results from a subset of samples. Vessel size estimates were based on a skeletonization algorithm that employs boundary-seeded and single-seeded distance transform techniques (Zhou, Y. et al., IEEE Trans.
  • mice are tested for assessing lytic bone metastasis.
  • Athymic (nude) mice were injected with a osteo-tropic subclone of the human breast CA line, MDA MB-231. After two weeks the bones are scanned to assess the cancer in the bone. The cancer is treated for two weeks and the lesions are imaged. The lesions are significantly smaller in mice treated with LPA, receptor antagonists such as VPC51299 or Kil6425 as described in Boucharaba, A., et al. (2006) Proc. Natl. Acad. Sci . v. 103, pp. 9643-9648. The results are illustrated in FIG. 13 .

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JP2009545531A (ja) 2006-07-24 2009-12-24 ユニバーシティ オブ バージニア パテント ファンデーション ホスホン酸ビニルリゾホスファチジン酸受容体拮抗薬
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ES2547124T3 (es) * 2009-04-02 2015-10-01 Merck Patent Gmbh Inhibidores de autotaxina
GB2470833B (en) 2009-06-03 2011-06-01 Amira Pharmaceuticals Inc Polycyclic antagonists of lysophosphatidic acid receptors
GB2474748B (en) 2009-10-01 2011-10-12 Amira Pharmaceuticals Inc Polycyclic compounds as lysophosphatidic acid receptor antagonists
WO2011159550A2 (fr) * 2010-06-14 2011-12-22 Amidra Pharmaceuticals, Inc. Antagoniste du récepteur de l'acide lysophosphatidique et ses utilisations
US20120094959A1 (en) 2010-10-19 2012-04-19 Bonnie Blazer-Yost Treatment of cystic diseases
EP2694496A1 (fr) 2011-04-05 2014-02-12 Amira Pharmaceuticals, Inc. Composés à base de 3- ou 5-biphényl-4-ylisoxazole utiles pour le traitement de la fibrose, de la douleur, du cancer et de troubles respiratoires, allergiques, de troubles du système nerveux ou de troubles cardiovasculaires
KR20140067048A (ko) 2011-08-15 2014-06-03 인터뮨, 인크. 라이소포스파티드산 수용체 길항제
WO2013070879A1 (fr) 2011-11-10 2013-05-16 Bristol-Myers Squibb Company Méthodes de traitement de lésion de la moelle épinière par des antagonistes du récepteur du lpa
AU2016270373A1 (en) 2015-06-05 2018-01-04 Vertex Pharmaceuticals Incorporated Triazoles for the treatment of demyelinating diseases
WO2018106641A1 (fr) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Pyrazoles pour le traitement de maladies démyélinisantes
WO2018106646A1 (fr) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Aminotriazoles pour traiter des maladies démyélinisantes
WO2018106643A1 (fr) 2016-12-06 2018-06-14 Vertex Pharmaceuticals Incorporated Azoles hétérocycliques pour le traitement de maladies de démyélinisation
JP7431435B2 (ja) * 2019-11-14 2024-02-15 国立大学法人大阪大学 新規リゾホスファチジン酸誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005115150A2 (fr) 2004-05-06 2005-12-08 University Of Virginia Patent Foundation Nouveaux antagonistes selectifs du recepteur de l'acide lysophosphatidique
WO2008014286A1 (fr) 2006-07-24 2008-01-31 University Of Virginia Patent Foundation Antagonistes du récepteur vinyle phosphonate acide lysophosphatidique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005115150A2 (fr) 2004-05-06 2005-12-08 University Of Virginia Patent Foundation Nouveaux antagonistes selectifs du recepteur de l'acide lysophosphatidique
WO2008014286A1 (fr) 2006-07-24 2008-01-31 University Of Virginia Patent Foundation Antagonistes du récepteur vinyle phosphonate acide lysophosphatidique

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"European Application Application No. 07813308.9, Office Action mailed Feb. 9, 2010", 2 pgs.
"European Application Application No. 07813308.9, Response filed Aug. 19, 2010 to Office Action mailedFeb. 9, 2010", 9 pgs.
"International Application Serial No. PCT/US2007/074262, International Search Report mailed Dec. 13, 2007", 3 pgs.
Cui, Peng, et al., "Synthesis and biological evalution of phostonate derivatives as autotaxin (STX) inhibitors", Bioorganic & Medical Chemistry Letters, vol. 17, No. 6, (Feb. 1997), 1634-1640.
Heasley, B. H, et al., "Initial structure-activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist.", Bioorg Med Chem Lett., 14(11), (Jun. 7, 2004), 2735-40.
Heasley, B.H., et al., "A novel series of 2-pyridyl-containing compounds as lysophosphatidic acid receptor antagonists: development of a nonhydrolyzable LPA3 receptor-selective antagonist", Bioorganic & Medicinal Chemistry Letters, vol. 14, No. 15, (Aug. 2004), 4069-4074.
Kassel, et al., "Different lysophosphatidic acid receptors mediate the direct stimulation of proliferation and the synegism with EGF in airway smooth muscle cells", ACTA Pharmacologica Sinica, vol. 27, No. Suppl. 1, (Jul. 2006), 379.

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